The researchers hypothesized that currently used doses of rituximab, of 375 mg/m2 or greater, significantly exceed the half-maximal effective dose of rituximab, at which differences between a biosimilar and the reference would be most likely to be found.
Among products that have thus far been candidates for biosimilar development, rituximab is unique in that it can be used in both oncology and rheumatology indications. However, dosing differs significantly for rituximab used in treating malignant versus nonmalignant disorders, and when rituximab is used off-label in treating immunological diseases, like multiple sclerosis, dosing schedules may vary even further.
This fact poses a challenge for demonstrating biosimilarity of a follow-on rituximab product in a patient population with nonmalignant disease, because no dose-finding trials are available in these indications, and it is as yet unclear which dose may be the most sensitive for detecting differences between proposed biosimilars and the reference rituximab.
A paper published in Scientific Reports describes 2 trials—an open-label, exploratory trial in healthy volunteers and a double-blind, randomized trial in healthy volunteers—that investigated the dose-response relationship of rituximab and a proposed biosimilar rituximab at low doses.
The researchers hypothesized that currently used doses of rituximab, of 375 mg/m2 or greater, significantly exceed the half-maximal effective dose of rituximab, at which differences between a biosimilar and the reference would be most likely to be found. Thus, their open-label trial assigned patients to receive either 0.1 mg/m2, 0.3 mg/m2, or 1.0 mg/m2 to identify the half-maximal effective dose of the reference product in vivo.
The trial enrolled 16 healthy volunteers, in whom rituximab depleted CD19-positive and CD20-positive cells from systemic circulation by the end of infusion. Mean CD20-positive cell counts decreased by approximately 97% in the 8 subjects in the 1-mg group, 74% in the 4 subjects in the 0.3-mg group, and 68% in the 4 subjects in the 0.1-mg group. Four weeks after infusion, CD20-positive cells returned to approximately 60% of baseline in the 1-mg group.
In the second trial, 36 volunteers were randomized to receive single infusions of either the reference rituximab or the proposed biosimilar at doses of either 0.1 mg/m2 or 0.3 mg/m2. Twelve participants each received the lower dose of the reference or the biosimilar, 8 received the higher dose of the biosimilar, and 4 received the higher dose of the reference.
In the lower-dose reference group, rituximab reduced the CD20-positive cell count by a mean of 48% (range, 25%-84%) and in the lower-dose biosimilar group, by a mean of 55% (range, 26%-85%).
In the higher-dose reference group, rituximab decreased CD20-positive cell counts by a mean of 81% (range, 67%-89%), and in the higher-dose biosimilar group, by a mean of 87% (range, 77%-96%).
The authors write that the half-maximal effective dose to deplete CD20-positive B cells with rituximab is 0.1 mg/m2, which represents “only a tiny fraction” of currently approved and used doses. Furthermore, they write, “Our results suggest that comparison of the effects of rituximab in the steep part of the dose-response curve is no longer possible when doses reach 1 mg/m2.” These findings will need to be verified in clinical trials involving patients, they add.
Schoergenhofer C, Schwameis M, Firbas C, et al. Single, very low rituximab doses in healthy volunteers—a pilot and a randomized trial: implications for dosing an biosimilarity testing. Sci Rep. 2018;8:124. doi: 10.1038/s41598-017-17934-6.